A great unmet need exists for pain therapies that are non-addictive and/or address pain that remains intractable to treatments available currently. Opiates, the most powerful drugs to treat pain, pose serious side effects and addictive potential and are sometimes ineffective. Two major non-opioid strategies to address pain are focused on either reducing inflammation and inflammatory pain (particularly relevant to arthritis) or reducing neural activity and neuropathic pain (particularly relevant to diabetes and nerve injury). There is emerging evidence to suggest that a ketogenic diet may alleviate pain. A ketogenic diet is a regimen that it is high in fat and low in carbohydrates, similar to the Atkins diet. The carbohydrate restriction decreases the metabolism of glucose and increases the metabolism of ketones. To date, the ketogenic diet has shown proven clinical efficacy in epilepsy and demonstrated basic research potential for neuroprotection in several types of acute and chronic brain injuries. A number of biochemical consequences of a ketogenic diet - decreased reactive oxygen species, decreased neural activity, increased adenosine and activation of peroxisome proliferator-activated receptors - all suggest that a ketogenic diet will be effective in increasing baseline pain thresholds and reducing both inflammatory and neuropathic pain. Our central hypothesis is that a ketogenic diet will alleviate pain, including intractable pain, based on its anti-inflammatory potential and akin to its success in treating intractable epilepsy. Despite multiple lines of evidence supporting our central hypothesis, the efficacy of a ketogenic diet in treating pain has not been tested either clinically or in animal models. The present objective is to test the effects of a ketogenic diet on baseline pain thresholds, inflammatory pain (Specific Aim 1) and neuropathic pain (Specific Aim 2). Testing our hypothesis in well-established animal models is feasible and may yield new therapeutic opportunities for pain relief and a new avenue for developing pain treatments that are both effective and non-addictive. PUBLIC HEALTH RELEVANCE: Chronic pain is a common and debilitating condition, strikingly reducing the costing the health care industry tens of billions of dollars annually. Evidence suggests that a ketogenic (very low carbohydrate/high fat) diet should provide relief in two types of chronic pain, inflammatory and neuropathic pain, found most commonly in rheumatoid arthritis and diabetes, respectively. This proposal will quantify the preventative and palliative effects of two ketogenic diets in well-characterized animal models of inflammatory and neuropathic pain.